1. Field of the Invention
The present invention is broadly directed to a method for inhibiting endothelial cell growth and capillary permeability associated with vascular endothelial growth factor (VEGF), e.g., the increased cell growth and permeability induced by VEGF using an inhibitor of the .beta. isozyme of Protein Kinase C (PKC). These VEGF induced conditions are closely associated with a variety of ocular vascular disorders.
The present invention is particularly directed to the use of an inhibitor of the .beta. isozyme of Protein Kinase C (PKC) for treating ocular vascular disorders including macular degeneration, macular edema, vascular retinopathy, retinal vein occlusion, iris neovascularization, histoplasmosis, and ischemic retinal diseases.
2. Description of Related Art
VPF/VEGF is a glycosylated, multifunctional cytokine. Over-expression of VPF/VEGF is associated with a variety of ocular vascular disorders.
VPF/VEGF induces endothelial cell proliferation, excessive permeability via activation of vesicular-vacuolar organelle mediated transport, migration and actin reorganization with shape changes and ruffling. It alters endothelial cell gene expression, inducing increased production of tissue factor and several proteases, including interstitial collagenase and both the urokinase-like and tissue plasminogen activators. The majority of these same genes are induced by phorbol myristate acetate (PMA) stimulated activation of PKC.
Vascular endothelial growth factor (VEGF) along with both fibroblast growth factors (FGFs) and transforming growth factor (TGF.beta.) are thought to play a major part in mediating active intraocular neovascularization in patients with ischemic retinal diseases (Aiello, et al., New England Jour. Medicine, 331(22):1480-1487 (1994); Amin, et al., Invest Ophthalmol Vis Sci., 35:3178-3188 (1994)).
One of the ocular vascular disorders associated with increased VEGF expression is macular degeneration. Age related macular degeneration is the leading cause of blindness in the elderly. It is estimated that macular degeneration afflicts more than 16% of people 85 and older, and 6% of people between the age of 65 and 74. Greater than 20% of patients over the age of 75 have macular degeneration. The disease is more frequent in women (Liebowitz H M, Krueer D E, Maunder L E, et al., "The Framingham Eye Study: VI Macular Degeneration," Surv. Opthalmol. 24 (supp 10:428-457, 1980); Klein, et al., "Prevalence of Age Related Maculopathy: The Beaver Dam Study," Ophthalmology, 99(6):933-943, 1992). Macular degeneration can be divided into dry or wet type, the dry type being 10 times more common, but generally less severe in its clinical manifestations. The more severe wet, or exudative macular degeneration, is associated with the abnormal growth of choroidal vessels (choroidal neovascularization) into the subretinal pigment epithelium or subretinal space and often leads to severe visual impairment.
Macular degeneration has the initial pathologic lesion of appearance of drusen which represents abnormal tissue deposition within the retinal pigment epithelial (RPE) layer and is thought to be secondary to vascular insufficiency. New blood vessels then grow through Bruch's membrane which is between the RPE and the choriocapillaries to invade the retina. This retinal invasion causes destruction of the photoreceptors and can lead to hemorrhage which reduces vision.
One of the most common forms of treatment for macular degeneration is laser therapy. Laser therapy is used to treat areas of neovascularization that do not extend into the central macular area (fovea). However, recurrence of the disease is common after laser therapy. (MPS Group, Arch Ophthalmol., Vol. 109, pp. 1232-1241 (1991)) Moreover, laser therapy can result in residual scotomata and therefore is not an optimal treatment of neovascularization in the central macular region. Only a limited number of patients meet eligibility criteria for this form of treatment, principally because of the ill-defined, or occult nature, of the choroidal neovascularization commonly seen. (Freund et al., Amer. Jour. Ophthalmol., 115:786-791 (1993)) Interferon also has been tried as a therapeutic agent based on the known activity of growth factors such as fibroblast growth factor on stimulation of pathologic angiogenesis. However, no consistent effect has been observed. (Kirkpatrick et al., Br. J. Ophthalmol., 77:766-770 (1993); Chan et al., Ophthalmology, 101:289-300 (1994)). More recently, a trial using transforming growth factor (TGF) beta-2 for treating macular degeneration was unsuccessfully concluded. Biotechnology Newswatch, Jan. 1, 1996.
With rapid aging of the population, macular degeneration poses a substantial public health problem. At present, there is no cure and the less than satisfactory results obtained with laser treatment is the only accepted therapy, though the FDA recently approved thalidomide for use in a clinical study with human patients. ("Researchers Focus on Macular Degeneration: Common Eye Problems, Causes and Treatment Get New Attention" by Steven Sternberg, Washington Post Health, Oct. 31, 1995). There remains a strong need in the art for an effective drug therapy for macular degeneration.
Macular edema is associated with many types of ocular vascular diseases, such as retinitis pigmentosa, diabetic retinopathy, pars planitis, retinal vein obstruction, senile hyalitis, and with intraocular surgical procedures (Henkind, Surv. Ophthalmol. 28;431-2 (1984); Bird, Surv. Ophthalmol., 28:433-6 (1984); Cunha-Vaz), Surv Ophthalmol. 28:485-92 (1984)). Cystoid macular edema is the most common complication following cataract surgery (Yannuzzi, Surv Ophthalmol. 28:540-53 (1984)) and probably the most common cause of visual loss in patients undergoing lens extraction (Jampol, et al., Surv. Ophthalmol. 28:535-9 (1984)). Cystoid macular edema is usually self-limited and even chronic cases can spontaneously improve (Yannuzzi, Surv Ophthalmol. 28:540-53 (1984)). However, a small proportion of patients (1 to 15%) may develop irreversible damage and permanent visual disability (Yannuzzi, et al., Opthalmology, 88:847-54 (1981)).
Macular edema is also a cause of late loss of vision in patients with the Vogt-Koyanagi-Harada (VKH) syndrome (Rutzen, et al., J. Ret. and Vit. Dis., 15(6):475-479 (1995)). Macular edema is closely associated with microaneurysms in diabetic retinopathy and in nondiabetic persons with sickle cell anemia, branch vein occlusion, carotid artery disease, or severe hypertension (Klein, Med Clin. N. Am., 72:1415-1437 (1989)). Microaneurysms often leak lipoprotein material, which results in the formation of hard exudates. These exudates appear in a scattered, aggregated, or ring-like configuration. When exudates and fluid collects in the posterior part of the retina, macular edema can result, which can cause significant blurring of vision and lead to loss of visual acuity.
A laser procedure, called focal photocoagulation, is used to treat the areas of retinal swelling adjacent to microaneurysms. Focal photocoagulation has been shown to decrease the incidence of deterioration of visual acuity by 60% in patients with clinically significant macular edema, but no benefit of photocoagulation has been shown in patients with mild-to-moderate macular edema (Raskin, et al., Ann. Int. Med, 117(3):226-233 (1992)). Vitreous surgery can improve the visual prognosis only in cases of diabetic macular edema associated with a pathological vitreo-macular interface (Vaneffenterre, et al., J. Francais D Ophtalmol., 16(11):602-610 (1993)). Drug treatments such as oral and topical indomethacin (Miwa, Drug Intell. Clin. Pharm., 20:548-550 (1986)), as well as erythropoietin (Friedman, et al., Amer. J. Kidney Dis., 26(1):202-208 (1995)) have been evaluated for macular edema but no significant effect has been observed. There is a need in the art for an effective drug therapy for macular edema.
While VEGF was known to play some role in the pathology of certain ocular vascular disorders, it remained to be determined whether inhibiting the function provided by VEGF would provide a therapeutic benefit to the treatement of such ocular vascular disorders. The present invention demonstrates that by inhibiting the activity of VEGF one can amelorate the pathology of a variety of these ocular vascular disorders.